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Despite the availability of factor replacement therapy, including prophylaxis, to treat and prevent bleeding, haemophilic arthropathy continues to be the most common complication of haemophilia and significantly impairs the quality of life in people with haemophilia (PwH). Regular periodic assessment of joint status in PwH is essential to identify early arthropathic changes and prevent the development or progression of haemophilic arthropathy. Kinematic and kinetic assessment are preferable and MRI is the gold standard for diagnosing haemophilic arthropathy, but availability is limited in developing countries. HJHS and ultrasound in conjunction with HEAD-US have been shown to effective in assessing changes indicating arthropathy.

Mixtures of recycled tyre aggregates and common granular geo-material such as gravel and sand have been widely used for various applications in geotechnical engineering, such as backfill, lightweight construction geomaterial and pavement subbase layers. The mechanical properties and characteristics of various soft-rigid granular blends has been extensively studied in the past. The main objective of these studies is to determine suitable mix designs for different applications and provide a better understanding of material response under applied loads. Experimental and numerical studies indicate the paramount importance of particle interaction at the microscale on the response of the soft-rigid granular mixtures at the macro scale. The stark contrast in stiffness (or flexibility) of soft tyre particles to rigid sand or gravel particles, means that in the soft-rigid mixtures under shearing or compressive loads, the deformation of soft tyre particles and continuous change of shape and contact area and hence constant evolution of frictional resistance plays an important role in the behaviour of these blends. In the present research mixtures of gravel and tyre particles in a range of volume ratios and size ratios were modelled using DEM (discrete element method) and calibrated to match one-dimensional compressibility experimental data obtained by the team. The effect of the shape of soft particles on the compressive response of soft-rigid granular mixtures is studied through rolling resistance in DEM. The role of rolling friction is studied in detail. Rolling resistance is found to be an important parameter to simulate the behaviour of the particle shape of these mixtures. Microscopic studies like spin analysis and share of contact force is performed to understand the observed response better. However, the increase in rolling resistance value beyond a calibrated value is found to have little impact on the macroscopic behaviour of these mixes.

Haemophilia is an inherited X-linked bleeding disorder characterised by a deficiency or absence of clotting factor VIII (haemophilia A) or IX (haemophilia B), which can cause musculoskeletal bleeding. The standard treatment for haemophilia is with factor concentrates to replace the missing or deficient clotting factor. However, there is a risk that the immune system develops antibodies against the exogenous factor, known as inhibitors. Managing patients with haemophilia and inhibitors who develop bleeding in unusual sites can be challenging for the treating physician. Here, we present a rare case of patient with severe haemophilia A who was diagnosed with inhibitors after developing bleeding in the left posterior chest wall (extra pleural haematoma). The patient was successfully managed with activated prothrombin complex concentrate (aPCC) (FEIBA: FVIII inhibitor bypassing activity; Baxter AG), and the pain and swelling gradually resolved over three weeks. This case emphasises the importance of clinical suspicion of inhibitor formation in a patient already diagnosed with haemophilia A presenting with unusual bleeding that does not respond to standard treatment.

In this paper we determine the normalized Laplacian spectrum of the Q-vertex corona, Q-edge corona, Q-vertex neighborhood corona, and Q-edge neighborhood corona of a connected regular graph with an arbitrary regular graph in terms of normalized Laplacian eigenvalues of the original graphs. Moreover, applying these results we find some non-regular normalized Laplacian co-spectral graphs.

Currently, in many cities around the world there is a significant increase in the number of vehicles, which leads to an aggravation of problems and contradictions in the road and transport system. This is especially true of traffic congestion, since the presence of the congestion leads to a number of negative consequences: an increase in travel time, additional fuel consumption and vehicle wear, stress and irritation of drivers and passengers, environmental poisoning and others. To solve the problem of congestion, it is necessary to have a reliable system for collecting information about the situation on the roads and a well-developed method for analyzing the collected information. The paper discusses the possibilities of collecting the required information using multi-touch video cameras and ways to improve them. A distinctive feature of this study is the registration of pedestrians crossing the road at the intersection. The aim of the work is to develop methods for collecting information using road sensor video surveillance systems in a traffic congestion and data processing using statistical methods such as: multiple regression analysis, cluster analysis, multidimensional scaling methods and others. The tasks were set: 1) to identify the most significant factors affecting the intensity of movement of vehicles at intersections in a congestion; 2) divide congestion into clusters with the identification of their characteristics; 3) to give a visual representation of multidimensional statistical information obtained with the help of multi-touch road video cameras.

The field of unsaturated soil mechanics has recently seen the introduction of pore network models, which attempt to replicate the void structure of porous materials. They are robust physically-based simulation tools and have been used to simulate constitutive relationships like soil water retention curves (SWRC) and unsaturated hydraulic conductivity functions. This work aims to present a pore networkmodeling approach for predicting hysteretic SWRC at various stress states using only grain size distribution and porosity data of the granular soils. The soil sample subjected to given stress conditions is simulated using the Discrete Element Method to obtain a stable packing of spherical particles representing the soil structure. From this packing, an algorithm based on the medial axis is availed to extract a network of pores and throats that describes the geometry and topology of the void structure of the granular soils. Various pore-scale mechanisms like the piston-like advance, corner flow, pore body filling, and snap-off are then used to model fluid displacements at the pore scale to simulate SWRC along the drying and wetting paths. The modeled SWRC under various stress conditions is compared with the measured curves obtained for granular soils from the literature, and the predictions are in good agreement with the experimental results.

Unsaturated soil mechanics is of keen relevance when dealing with soil above the water table orcompacted soils. Barcelona Basic Model (BBM) is one of the most widely used constitutive models for describing unsaturated soil behaviour and is available as a soil model in software like PLAXIS and CODE_BRIGHT (developed by UPC). The present study demonstrates a numerical framework to implement BBM within the ABAQUS package as a user-defined soil model using a user subroutine called UMAT (User Material). The backward Euler integration scheme coupled with Newton Raphson iterative algorithm is used to construct the model. A convergence test is conducted to check the accuracy and stability of the integration. UMAT's inability to manage pore pressure led to proxy diffusion to depict suction variation. The heat equation is used as a proxy for diffusion in three-dimensional space and time. Anoedometer test is simulated in which the soil is allowed to consolidate and then set to saturate at constant vertical stress, which leads to wetting collapse. The results demonstrate a reasonable behaviour of wettinginduced compression of soil subjected to loading with varying saturation level.

We have estimated the rate of production of lepton pairs from a magnetised hot and dense QCD medium. We get rid of all kinds of previously considered approximations in terms of the strength of the magnetic field as well as the components of the momentum of the emitted lepton pairs. We find an enhancement in the rate in presence of an arbitrary strength of the magnetic field. With further consideration of an effective model scenario, we find the appearance of a gap in the rate. The implications of such a gap and other quasi-quark effects on the rate have been investigated in detail.

The R-graph R(G) of a graph G is the graph obtained from G by intro- ducing a new vertex ue for each e ∈ E(G) and making ue adjacent to both the end vertices of e. In this paper, we determine the adjacency, Lapla- cian and signless Laplacian spectra of R-vertex join and R-edge join of a connected regular graph with an arbitrary regular graph in terms of their eigenvalues. Moreover, applying these results we construct some non-regular A-cospectral, L-cospectral and Q-cospectral graphs, and find the number of spanning trees.

Particle Size Distribution (PSD) is one of the prime guiding factors of granular media response. Degradation via weathering is a process, which brings about a gradual shift in the PSD. In nature, chemically sensitive material like calcite undergoes chemo-mechanical degradation bringing about variations in their behaviour. In the present study, an experimental investigation is carried out to get insight into the mechanical response during the coupled chemo-mechanical process. The experiments were carried out at two different rates of dissolutions in a custom made 1D compression mould. From the experiments, it is clear that the higher rate of dissolution reduces the lateral earth pressure more than the lower rate. Discrete Element Method (DEM) analyses the micromechanical process behind the observed response from experiments. The results showed a reduction in lateral stress as soon as the dissolution starts. DEM analysis confirms the competing mechanism between grain size reduction and grain rearrangement as the guiding element for the granular media response.

Under a postulated scenario of Loss of Coolant Accident (LOCA) with un-availability of emergency core cooling system (ECCS) for Indian Pressurized Heavy Water Reactor (IPHWR), the channel integrity needs to be assured. An experimental facility is presently being developed at Indian Institute of Technology Roorkee (IIT R) India to study such a severe event. In this study a CFD simulation of fuel bundle weight simulator is being carried out using ANSYS 19.0 in transient thermal analysis using ANSYS Parametric Design Language (APDL) solver. The test facility aims to estimate the thermal aspect of weight bundle simulator which is the source of heat generation for pressure tube. Thermo-mechanical deformation of pressure tube will depend on the heat source, therefore it is of great importance to check the thermal integrity of weight bundle fuel simulator. Power requirement, weight, and dimensions of weight bundle fuel simulator is similar to the actual fuel bundle used in 700 MWe IPHWR. Simulation was done for 3 % and 2% decay heat. From analysis it was found that the rate of temperature rise in pressure tube with 3 % decay heat reached a maximum of 2 0C/sec and average rate of temperature rise was around 1 0C/sec whereas with 2% decay heat, pressure tube maximum temperature rise was 1.5 0C/sec and average rate 0.8 0C/sec. Results obtained will be further used for designing of 700 MWe full length channel set-up.

Shale rock consists of a complex matrix structure due to presence of nano-scale pores. Owing to such complexity determination and/or prediction of the mineralogical, mechanical, and petrophysical properties (e.g., permeability, porosity, pore size distribution, etc.) of shale is a challenging task. A preliminary estimation of these properties is essential before shale gas exploration. In this study, experimental and numerical analyses are conducted to estimate the permeability, porosity, and pore size distribution of a typical shale sample. Gas adsorption experiments were conducted to characterize the pore spaces of the shale via analysing the isotherms. Using conventional theories, such as BET and BJH methods, surface area, pore volume, and pore size distributions were estimated. On the other hand, gross porosity of the shale samples was measured by conducting gas pycnometry experiment. Finally based on the obtained results an equivalent pore network model is constructed which accounts for the pore size distributions and low pore connectivity in the shale matrix. We have simulated gas flow through the network to estimate permeability of the shale. This model considers Knudsen diffusion and the effects of gas slippage on permeability. Further parametric study shows that the apparent permeability primarily depends on the reservoir pressure, pore coordination number and porosity.

Pore size distribution is an important feature of granular materials in the context of filtration and erosion in soil hydraulic structures. Present study focuses on the evolution characteristics of pore size distribution for numerically simulated granular assemblies while subjected to various compression boundary constrain, namely, conventional drained triaxial compression, one-dimensional or oedometric compression and isotropic compression. We consider the effects initial packing of the granular assembly, loose or dense state. A simplified algorithm based on Delaunay tessellation is used for the estimation of pore size distribution for the deforming granular assemblies at various stress states. The analyses show that, the evolution of pore size is predominantly governed by the current porosity of the granular assembly while the stress path or loading process has minimal influence. Further it has also been observed that pore volume distribution reaches towards a critical distribution at the critical porosity during shear enhanced loading process irrespective of the deformation mechanism either compaction or dilation.

Abstract Background Stepping Stones training aims to help individuals explore sexual relationships and recognize gender inequalities, the structural drivers of the HIV epidemic, in order to understand risk behaviours and to seek solutions to factors that increase HIV vulnerability. Despite earlier studies suggesting the success of Stepping Stones, little data exist to show diffusion to trainees' social networks or the wider community. Methods A mixed-methods evaluation of this approach was undertaken using in-depth interviews of trainees and friends, and polling booth surveys in 20 villages where Stepping Stones training took place and in another 20 villages with no Stepping Stones intervention. Results The interview respondents and their friends reported significant changes in their relationships after training, and benefit from discussion of gender, sexuality, condom use and HIV vulnerability issues. However, though diffusion of this knowledge at the level of personal contacts was strong, the evaluation revealed that diffusion to the community level was limited. Conclusions The qualitative part of this study reflects other studies in different settings, in that SS participants gained immensely from the training. Wider behaviour change is a challenging goal that many programmes fail to attain, with most interventions too limited in scope and intensity to produce larger community effects. This may have contributed to the fact that we observed few differences between interventions and non-intervention villages in this study. However, it is also possible that we had excessive expectations of individual change at the community level, and that it might have been more appropriate to have had broader community level rather than individual behavioural change indicators. We suggest that SS could be enhanced by efforts to better engage existing community opinion leaders, to empower and train participants as community change agents, and to support the development of village-level action plans that combat sexual stereotyping and risky behaviours that lead to unhealthy sexual relationships.

Abstract Background Quantum dots (QDs) are crystalline nanoparticles that are compatible with biological systems to provide a chemically and photochemically stable fluorescent label. New ligand probes with fluorescent reporter groups are needed for detection and characterization of G protein-coupled receptors (GPCRs). Results Synthetic strategies for coupling the A2A adenosine receptor (AR) agonist CGS21680 (2-[4-(2-carboxyethyl)phenylethylamino]-5'-N-ethylcarboxamidoadenosine) to functionalized QDs were explored. Conjugates tethered through amide-linked chains and poly(ethyleneglycol) (PEG) displayed low solubility and lacked receptor affinity. The anchor to the dendron was either through two thiol groups of (R)-thioctic acid or through amide formation to a commercial carboxy-derivatized QD. The most effective approach was to use polyamidoamine (PAMAM) D5 dendrons as multivalent spacer groups, grafted on the QD surface through a thioctic acid moiety. In radioligand binding assays, dendron nucleoside conjugate 11 displayed a moderate affinity at the human A2AAR (Kiapp 1.02 ± 0.15 μM). The QD conjugate of increased water solubility 13, resulting from the anchoring of this dendron derivative, interacted with the receptor with Kiapp of 118 ± 54 nM. The fluorescence emission of 13 occurred at 565 nm, and the presence of the pendant nucleoside did not appreciably quench the fluorescence. Conclusions This is a feasibility study to demonstrate a means of conjugating to a QD a small molecular pharmacophore of a GPCR that is relatively hydrophobic. Further enhancement of affinity by altering the pharmacophore or the linking structures will be needed to make useful affinity probes.

Abstract Background The chromosomes of higher plants are littered with retrotransposons that, in many cases, constitute as much as 80% of plant genomes. Long terminal repeat retrotransposons have been especially successful colonizers of the chromosomes of higher plants and examinations of their function, evolution, and dispersal are essential to understanding the evolution of eukaryotic genomes. In soybean, several families of retrotransposons have been identified, including at least two that, by virtue of the presence of an envelope-like gene, may constitute endogenous retroviruses. However, most elements are highly degenerate and are often sequestered in regions of the genome that sequencing projects initially shun. In addition, finding potentially functional copies from genomic DNA is rare. This study provides a mechanism to surmount these issues to generate a consensus sequence that can then be functionally and phylogenetically evaluated. Results Diaspora is a multicopy member of the Ty3-gypsy-like family of LTR retrotransposons and comprises at least 0.5% of the soybean genome. Although the Diaspora family is highly degenerate, and with the exception of this report, is not represented in the Genbank nr database, a full-length consensus sequence was generated from short overlapping sequences using a combination of experimental and in silico methods. Diaspora is 11,737 bp in length and contains a single 1892-codon ORF that encodes a gag-pol polyprotein. Phylogenetic analysis indicates that it is closely related to Athila and Calypso retroelements from Arabidopsis and soybean, respectively. These in turn form the framework of an endogenous retrovirus lineage whose members possess an envelope-like gene. Diaspora appears to lack any trace of this coding region. Conclusion A combination of empirical sequencing and retrieval of unannotated Genome Survey Sequence database entries was successfully used to construct a full-length representative of the Diaspora family in Glycine max. Diaspora is presently the only fully characterized member of a lineage of putative plant endogenous retroviruses that contains virtually no trace of an extra coding region. The loss of an envelope-like coding domain suggests that non-infectious retrotransposons could swiftly evolve from infectious retroviruses, possibly by anomalous splicing of genomic RNA.

Abstract Background Glioblastoma is the deadliest and most prevalent brain tumor. Dexamethasone (DXM) is a commonly used steroid for treating glioblastoma patients for alleviation of vasogenic edema and pain prior to treatment with chemotherapeutic drugs. Temozolomide (TMZ), an alkylating agent, has recently been introduced in clinical trials for treating glioblastoma. Here, we evaluated the modulatory effect of DXM on TMZ induced apoptosis in human glioblastoma U87MG cells. Results Freshly grown cells were treated with different doses of DXM or TMZ for 6 h followed by incubation in a drug-free medium for 48 h. Wright staining and ApopTag assay showed no apoptosis in cells treated with 40 μM DXM but considerable amounts of apoptosis in cells treated with 100 μM TMZ. Apoptosis in TMZ treated cells was associated with an increase in intracellular free [Ca2+], as determined by fura-2 assay. Western blot analyses showed alternations in the levels of Bax (pro-apoptotic) and Bcl-2 (anti-apoptotic) proteins resulting in increased Bax:Bcl-2 ratio in TMZ treated cells. Western blot analyses also detected overexpression of calpain and caspase-3, which cleaved 270 kD α-spectrin at specific sites for generation of 145 and 120 kD spectrin break down products (SBDPs), respectively. However, 1-h pretreatment of cells with 40 μM DXM dramatically decreased TMZ induced apoptosis, decreasing Bax:Bcl-2 ratio and SBDPs. Conclusion Our results revealed an antagonistic effect of DXM on TMZ induced apoptosis in human glioblastoma U87MG cells, implying that treatment of glioblastoma patients with DXM prior to chemotherapy with TMZ might result in an undesirable clinical outcome.

A unified method toward the synthesis of functionalized diazepines and quinazolines through reorganization of the molecular skeleton has been devised. The process is indulged by electrical energy via a domino N 1 -N 2 bond cleavage followed by concomitant ring closing, initiating from cinnolines and indazoles as designed precursors. Additionally, an intermolecular ring homologation has also been established to synthesize densely functionalized dihydroquinazolines from 2,3-diaryl-indazoles and acetonitrile involving the same electrochemical strategy.

A metal-free approach for synthesizing hybrid quinoxaline derivatives from sulfoxonium ylide and a 1,5-bis-nucleophilic N-heterocycle mediated by elemental sulfur is presented to illuminate the [5+1] cascade cyclization sequence. Large-scale synthesis and postsynthetic functionalizations for the annulative π-extension and intramolecular aza-annulation reactions reveal the potential utility and actualize the fabricated approach.

Background: Postacute sequelae of COVID-19 (PASC) remain understudied in nonhospitalized patients. Digital wearables allow for a continuous collection of physiological parameters such as respiratory rate and oxygen saturation that have been predictive of disease trajectories in hospitalized patients., Objective: This protocol outlines the design and procedures of a prospective, longitudinal, observational study of PASC that aims to identify wearables-collected physiological parameters that are associated with PASC in patients with a positive diagnosis., Methods: This is a single-arm, prospective, observational study of a cohort of 550 patients, aged 18 to 65 years, male or female, who own a smartphone or a tablet that meets predetermined Bluetooth version and operating system requirements, speak English, and provide documentation of a positive COVID-19 test issued by a health care professional within 5 days before enrollment. The primary end point is long COVID-19, defined as ≥1 symptom at 3 weeks beyond the first symptom onset or positive diagnosis, whichever comes first. The secondary end point is chronic COVID-19, defined as ≥1 symptom at 12 weeks beyond the first symptom onset or positive diagnosis. Participants must be willing and able to consent to participate in the study and adhere to study procedures for 6 months., Results: The first patient was enrolled in October 2021. The estimated year for publishing the study results is 2025., Conclusions: This is a fully decentralized study investigating PASC using wearable devices to collect physiological parameters and patient-reported outcomes. The study will shed light on the duration and symptom manifestation of PASC in nonhospitalized patient subgroups and is an exemplar of the use of wearables as population-level monitoring health tools for communicable diseases., Trial Registration: ClinicalTrials.gov NCT04927442; https://clinicaltrials.gov/study/NCT04927442., International Registered Report Identifier (irrid): DERR1-10.2196/57382., (©Sherine El-Toukhy, Phillip Hegeman, Gabrielle Zuckerman, Anirban Roy Das, Nia Moses, James Troendle, Tiffany M Powell-Wiley. Originally published in JMIR Research Protocols (https://www.researchprotocols.org), 16.08.2024.)

Distinct protocols have been devised for the preparation of hybrid heterocyclic scaffolds like π-extended pyrido-acridines and quinazolino-phenanthridines duly materialized through Rh(III)- and Pd(II)-mediated catalytic courses commencing from acridine and quinazolimine scaffolds. Interestingly, the parent compounds (acridines and quinazolimines) are actualized from 2-aminobenzonitrile and anthranilic acid, where 2-aminobenzonitrile acts as the 1,4-dipolarophilic species and anthranilic acid as the benzyne precursor. The molecular assembly of acridine suggests the participation of two benzyne units. In addition, the structural motif of the quinazolimine ring features one benzyne unit. Further, indolizine ring containing the enaminonitrile skeleton upon exposure to benzyne forms an indolizine fused quinoline ring, decorated with three benzyne units.

Two structurally distinct and biologically privileged succinimide and isoindole heteroarenes bearing benzothiadiazinedioxide motif-centered hybrid conjugates are proficiently achieved through Rh(III)-catalyzed sequential C(sp 2 )-H bond activation, ortho -alkenylation and finally cascade intramolecular cyclization. The significant feature of this developed protocol is that the resulting diversely decorated heterocycles contain a quaternary carbon center and this has been coursed through atypical [4 + 1] annulation ignoring the prevalent [4 + 2]-cyclization pathway and interestingly the applied coupling partners (e.g., maleimide, maleate, and styrene) to materialize the protocol functioned only as C1 synthon. Furthermore, the selective reduction strategy enables to modify the hybrid conjugate of succinimide and benzothiazine dioxide to benzothiazine dioxide-based spirocyclic isoindolopyrrolidinedione skeleton following preferential reduction of one carbonyl group of imide functionality. Overall this methodology emerges to be easily handled, versatile, time-efficient, and manifests relatively unfamiliar spiro-cyclization and good functional group tolerance so easy to grab a library of the entirely new variant of decorated hybrid spiro-heterocyclic scaffolds.

Salmonella spp., a leading cause of foodborne illness, is a formidable global menace due to escalating antimicrobial resistance (AMR). The evaluation of minimum inhibitory concentration (MIC) for antimicrobials is critical for characterizing AMR. The current whole genome sequencing (WGS)-based approaches for predicting MIC are hindered by both computational and feature identification constraints. We propose an innovative methodology called the "Genome Feature Extractor Pipeline" that integrates traditional machine learning (random forest, RF) with deep learning models (multilayer perceptron (MLP) and DeepLift) for WGS-based MIC prediction. We used a dataset from the National Antimicrobial Resistance Monitoring System (NARMS), comprising 4500 assembled genomes of nontyphoidal Salmonella , each annotated with MIC metadata for 15 antibiotics. Our pipeline involves the batch downloading of annotated genomes, the determination of feature importance using RF, Gini-index-based selection of crucial 10-mers, and their expansion to 20-mers. This is followed by an MLP network, with four hidden layers of 1024 neurons each, to predict MIC values. Using DeepLift, key 20-mers and associated genes influencing MIC are identified. The 10 most significant 20-mers for each antibiotic are listed, showcasing our ability to discern genomic features affecting Salmonella MIC prediction with enhanced precision. The methodology replaces binary indicators with k-mer counts, offering a more nuanced analysis. The combination of RF and MLP addresses the limitations of the existing WGS approach, providing a robust and efficient method for predicting MIC values in Salmonella that could potentially be applied to other pathogens.

Comparison of gap arthroplasty (GAP), interpositional arthroplasty (IAP) and distraction osteogenesis (DO) simultaneous with interpositional arthroplasty (DO+IAP) in management of TMJ ankylosis is of interest to dentists. The study comprised 36 individuals with TMJ ankylosis, 16 of whom were female and 20 of whom were male. Both prior to and following surgery, the maximum inter-incisal opening (MIO) and facial pattern were noted. The postoperative MIO was 33.23 ± 1.23mm, 35.24 ± 1.11mm and 38.24 ± 1.34mm in GAP, IAP and DO+IAP respectively. Data is statistically significant with high MIO observed in DO+ IAP technique and low MIO in GAP technique (p < 0.005). In addition to lengthening the mandible, concurrently processed interpositional arthroplasty alongside DO for TMJ ankylosis corrects gross asymmetry of the face, occlusal mal-alignment, midline change, and creates room for previously un-erupted teeth to emerge., (© 2023 Biomedical Informatics.)

Efficacious protocols have been established to synthesize a structurally privileged Π-extended coumarin-fused pyridone nucleus by activating the vinylic C(sp 2 )-H bond of coumarin-3-carboxamide under the influence of inexpensive Ru(II)-metal. Here an N -methoxy carboxamide entity has been exploited as the chelating fragment to manifest C(sp 2 )-H bond functionalization with a concomitant (4 + 2) annulation reaction, resulting in heterocyclic ring-forming protocols along with sulfoxonium ylide and iodonium ylide as representative bench-stable carbene surrogates. This diverse heterocycle formation via carbene insertion strategies, is further expanded to activate the ortho -C(sp 2 )-H bonds of different heterocycles by employing the sp 2 -N moiety as the directing group to develop acyl-alkylated/alkenylated quinazolines, isoxazoles and highly fluorescent pyridone- N -oxides. Intriguingly, during an evaluation of the versatility of the current protocols, a one-pot double C-H activation has been rationalized in the presence of iodonium ylide, which results in biologically potent benzimidazole-fused coumarin-centered bridge-headed polycyclic heteroarenes. Furthermore, a chemo-selective late-stage synthetic transformation is being designed to develop differently substituted pyridone analogues by switching the nature of the reducing agent. In addition, a photophysical experiment was done on one pyridine- N -oxide compound (7e) and delightfully it exhibited fluorescence quenching activity selectively in the presence of Al 3+ ions, which appears to be a unique feature of our methodology. Finally, upon correlation of the merit of the developed pathways, the iodonium ylide mediated strategy appears to be superior.

An efficient and fascinating protocol has been devised for the preparation of fused furan moieties involving a Rh(II) catalyzed one-pot C-H activation/concomitant tandem annulation process, employing an enolic compound and β-keto sulfoxonium ylide as the reacting conjugates. The developed technique demands only Rh 2 (TFA) 4 as the catalyst to proceed forward and is devoid of additional metallic or nonmetallic additives. The skeletal transformation of naphthoquinone fused furan to highly decorated naphthoquinone fused indolizines is a promising synthetic application.

Quinazoline moieties and particularly C4-substituted quinazoline scaffolds are widely distributed in biologically active molecules, and thus, direct C4-functionalization of quinazolines is the most convenient way to materialize new, straightforward, and sustainable strategies for the synthesis of useful medicinal targets. Retrospecting that, effort has been directed toward electrocatalytic C4-H bond diversification of quinazoline and related electron-deficient N-heterocycles (quinoxaline) offering C4 and C3 benzoyl-, acetyl-, phenol-, ether-, phosphonate-, and nitroalkane-incorporated N-heterocycles via a radical addition pathway under sacrificial oxidant- and additive-free conditions. Various coupling partners and quinazolines, as well as other structurally similar heterocyclic motifs, respond well, providing moderate to high yields of coupled products along with the gram-scale upgradation. Additionally, the performed control experiments and cyclic voltammetry investigations also nicely justified the proposed mechanism of the coupling process. Further, late-stage functionalization leading to the synthesis of indolo quinolines and vinyl-sulfonated products using the ruthenium-catalyzed skeletal transformation of benzoylated quinazoline 3b nicely appropriated the developed methodology. Finally, this reaction can be summarized as (a) anodic activation of the functionalized Hantzsch ester to furnish key radical species; (b) radical addition to an activated N-heterocycle; and (c) oxidation leading to the target product without the assistance of any metal chelation.

In recent days, the hike in obesity-mediated epidemics across the globe and the prevalence of obesity-induced cardiovascular disease has become one of the chief grounds for morbidity and mortality. This epidemic-driven detrimental events in the cardiac tissues start with the altered distribution and metabolism pattern of high-density lipoprotein and low-density lipoprotein (LDL) leading to cholesterol (oxidized LDL) deposition on the arterial wall and atherosclerotic plaque generation, followed by vascular spasms and infarction. Subsequently, obesity-triggered metabolic malfunctions induce free radical generation which may further trigger pro-inflammatory signaling and nuclear factor kappa-light-chain-enhancer of activated B cells transcriptional factor, thus inducing interferon-gamma, tumor necrosis factor-alpha, and inducible nitric oxide synthase. This terrifying cardiomyopathy can be further aggravated in type 2 diabetes mellitus, thereby making obese diabetic patients prone toward the development of myocardial infarction (MI) or stroke in comparison to their nondiabetic counterparts. The accelerated oxidative stress and pro-inflammatory response induced cardiomyocyte hypertrophy, followed by apoptosis in obese diabetic individuals, causing progression of athero-thrombotic vascular disease. Being an efficient antioxidative and anti-inflammatory indolamine, melatonin effectively inhibits lipid peroxidation, pro-inflammatory reactions, thereby resolving free radical-induced myocardial damages along with maintaining antioxidant reservoir to preserve cardiovascular integrity. Prolonged melatonin treatment maintains balanced body weight and serum total cholesterol concentration by inhibiting cholesterol synthesis and promoting cholesterol catabolism. Additionally, melatonin promotes macrophage polarization toward the anti-inflammatory state, providing a proper shield during the recovery period. Therefore, the protective role of melatonin in maintaining the lipid metabolism homeostasis and blocking the atherosclerotic plaque rupture could be targeted as the possible therapeutic strategy for the management of obesity-induced acute MI. This review aimed at orchestrating the efficacy of melatonin in ameliorating irrevocable oxidative cardiovascular damage induced by the obesity-diabetes correlation., (© 2022 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

An efficient protocol has been developed for the preparation of π-extended N-heterocycles involving a Rh(III)-catalyzed C-H activation reaction starting from 3-acetamidocoumarins and internal alkynes. The isolation of the intermediate pyrrolo-coumarin suggests that the -COCH 3 group in acetamidocoumarins performs the role of a traceless directing group. Besides, the use of commercially available [Cp*RhCl 2 ] 2 adds more importance as no additional modification of the catalyst is required. A two-step protocol bearing intermediate pyrrolo-coumarin can be further functionalized to highly decorated heterocyclic moieties materializing sp 2 C-H and sp 2 N-H coupling. Moreover, one of the pyrrolo-coumarin compounds ( 3da ) is capable of differentiating between Cr(III) and Cr(VI) ions as revealed via fluorescence spectroscopy. In addition, intermediate pyrrolo-coumarin is further functionalized to spirocyclic N-heterocycles.

Herein, we report a practical and simple mono- and di-C(sp 3 )-O cross-coupling of tautomerizable N-heterocycles (dihydrophthalazine-1,4-diones, pyridone, quinoxalinone and pyrimidinone) with ketones, β-dicarbonyl compounds and nitroalkane, leading to substituted imidate derivatives under visible-light conditions. The combination of rose bengal as the photocatalyst and TBHP enables sustainable reaction conditions, operational simplicity, and high chemo- and regioselectivity with exceptional yields (up to 94%), good functional group tolerance and substrate generality. In the case of unsymmetrical ketones, the less substituted end is functionalized selectively. The di-C-O coupling products are generally obtained with ketones containing three enolizable 'H' at the reaction site while ketones with two enolizable 'H' furnished only single coupling products. Radical inhibition experiments revealed the involvement of a radical pathway in this coupling strategy. The coupling products are also scaled up to the gram scale, offering scope for further functionalizations via C-H bond activation.

An expeditious synthetic route to access functionalized pyrrolo[2,1- b ]quinazoline scaffolds has been achieved via domino ring opening cyclization (DROC) reactions of donor-acceptor (D-A) cyclopropanes and 2-amino(methyl)aniline derivatives. This novel iron catalyzed transformation is amenable to a wide range of substrates. Three new C-N bonds and two rings were sequentially constructed in this divergent one-pot process. The advantages of simple operation, high yields and general applicability make this procedure highly attractive and practical too.

Introduction: The low-level laser therapy has been accepted globally as cell bio-modulator, used to reach ideal therapeutic effects, acting in the reduction of the pain response, with anti-inflammatory effects, stimulating local micro-circulation and wounds repair, promoting a rapid recovery, which brings a better quality of life to the patient. In this study, we aim to to determine the effectiveness of low-level laser therapy on reducing the pain and swelling after removal of impacted third molars., Materials and Methods: In this present prospective randomized clinical study, third molar surgeries were performed in thirty patients who were divided into two equal groups (placebo group and study group) a placebo group with routine treatment and a study group with low-level laser therapy which was applied both intraorally and extraorally after the surgical extraction of mandibular third molar., Results: The parameters such as postoperative pain, edema, and trismus were assessed on 1 st and 7 th day. All these parameters showed statistically significant results in patients with low-level laser therapy., Conclusions: Low-level laser therapy was effective in reducing the postoperative pain, edema, and trismus in the third molar surgeries., (Copyright: © 2022 National Journal of Maxillofacial Surgery.)

An efficient palladium catalyzed diastereoselective addition of arylboronic acids to complex spirocyclopropyl dinitriles is developed in the presence of a catalytic amount of 4-dodecylbenzenesulphonic acid (DBSA) as a Brønsted acid surfactant in aqueous media. The protocol is also found to be highly effective when different types of nitrile compounds and organo-boron compounds are used. The overall reaction has been found to be very cost efficient since it requires low catalyst loading, mild thermal energy and short reaction time. Wide substrate scope, operational simplicity, good to excellent product yield, and use of green solvents make the reaction a practical route to transform nitrile into a keto functionality in biorelevant heterocyclic scaffolds. The scale-up synthesis of the target scaffolds can also be achieved with ease which also signifies the practicability of this protocol.

Aims: Preventing mitochondrial dysfunction and enhancing mitochondrial health and biogenesis is a crucial therapeutic approach to ameliorate injury following acute myocardial infarction. Although the antioxidant role of melatonin against ischemia/reperfusion injury has been reported, the exact mechanism of protection, in vivo , remains poorly understood. This study aims to identify and elaborate upon mechanism of melatonin protection of rat cardiac mitochondria against acute myocardial infarction., Main Methods: Rats were pre-treated with melatonin (10 mg/kg body weight (b.w.); intraperitoneally, i.p.) before isoproterenol bitartrate (ISO) administration (25 mg/kg body weight (b.w.) subcutaneously,s.c.) and their effect on rat heart mitochondrial structure and function was studied. Biochemical changes in activity of biomarkers of oxidative stress, antioxidant enzymes as well as Krebs' cycle enzymes were analyzed. Gene expression studies and Isothermal titration calorimetric studies with pure catalase and ISO were also carried out., Key Findings: Melatonin was shown to reduce ISO induced oxidative stress, by stimulating superoxide dismutase activity and removing the inhibition of Krebs' cycle enzymes. Herein we report for the first time in rat model that melatonin activates the SIRT1-PGC-1α-SIRT3 signaling pathways after ISO administration, which ultimately induces mitochondrial biogenesis. Melatonin exhibited significant protection of mitochondrial architecture and topology along with increased calcium ion permeability and reactive oxygen species (ROS) generation induced by ISO. Isothermal calorimetric studies revealed that melatonin binds to ISO molecules and sequesters them from the reaction thereby limiting their interaction with catalase along with occupying the binding sites of catalase themselves., Significance: Activation of SIRT1-PGC-1α-SIRT3 pathway by melatonin along with its biophysical properties prevents ISO induced mitochondrial injury in rat heart., (© 2020 The Authors.)